tbuckley/cabot-search huggingface dataset:
When I use a word . . . . Medical counterfactuals
Authors: Jeffrey K Aronson
Journal: BMJ (2022)

A counterfactual statement or narrative, originally a philosophical concept, expresses an assessment of what might have happened if certain unfulfilled conditions had actually occurred. "If <i>this</i> happened [instead of what actually happened] <i>that</i> would have occurred as a result [instead of what actually occurred]." In this statement, the protasis ["If <i>this</i> happened"] is false and the apodosis ["<i>that</i> would have occurred …"] is therefore indeterminable. The use of counterfactual ideas is a popular device in fiction, and there are many examples. However, some regard counterfactual speculation as more than just an entertaining game, considering it also a mode of historical analysis, which might, for example, promote reflection on past actions, suggest possible causes of outcomes, and lead to different actions in the future, or lead to the repetition of previously successful strategies, avoiding other possibilities. In medical practice counterfactual considerations are relevant to the testing of hypotheses, the conduct of clinical trials, and the use of the Precautionary Principle when contemplating preventive or therapeutic interventions.
Endovascular ablation of the right greater splanchnic nerve in heart failure with preserved ejection fraction: early results of the <scp>REBALANCE‐HF</scp> trial roll‐in cohort
Authors: Marat Fudim, Peter S. Fail, Sheldon E. Litwin, Tamaz Shaburishvili, Parag Goyal, Scott L. Hummel, Barry A. Borlaug, Rajeev C. Mohan, Ravi B. Patel, Sumeet S. Mitter, Liviu Klein, Krishna Rocha‐Singh, Manesh R. Patel, Vivek Y. Reddy, Daniel Burkhoff, Sanjiv J. Shah
Journal: European Journal of Heart Failure (2022)

Aims In heart failure (HF) with preserved ejection fraction (HFpEF), excessive redistribution of blood volume into the central circulation leads to elevations of intracardiac pressures with exercise limitations. Splanchnic ablation for volume management (SAVM) has been proposed as a therapeutic intervention. Here we present preliminary safety and efficacy data from the initial roll‐in cohort of the REBALANCE‐HF trial. Methods and results The open‐label (roll‐in) arm of REBALANCE‐HF will enrol up to 30 patients, followed by the randomized, sham‐controlled portion of the trial (up to 80 additional patients). Patients with HF, left ventricular ejection fraction (LVEF) ≥50%, and invasive peak exercise pulmonary capillary wedge pressure (PCWP) ≥25 mmHg underwent SAVM. Baseline and follow‐up assessments included resting and exercise PCWP, New York Heart Association (NYHA) class, Kansas City Cardiomyopathy Questionnaire (KCCQ), 6‐min walk test, and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP). Efficacy and safety were assessed at 1 and 3 months. Here we report on the first 18 patients with HFpEF that have been enrolled into the roll‐in, open‐label arm of the study across nine centres; 14 (78%) female; 16 (89%) in NYHA class III; and median (interquartile range) age 75.2 (68.4–81) years, LVEF 61.0 (56.0–63.2)%, and average (standard deviation) 20 W exercise PCWP 36.4 (±8.6) mmHg. All 18 patients were successfully treated. Three non‐serious moderate device/procedure‐related adverse events were reported. At 1‐month, the mean PCWP at 20 W exercise decreased from 36.4 (±8.6) to 28.9 (±7.8) mmHg ( p &lt; 0.01), NYHA class improved by at least one class in 33% of patients ( p = 0.02) and KCCQ score improved by 22.1 points (95% confidence interval 9.4–34.2) ( p &lt; 0.01). Conclusion The preliminary open‐label results from the multicentre REBALANCE‐HF roll‐in cohort support the safety and efficacy of SAVM in HFpEF. The findings require confirmation in the ongoing randomized, sham‐controlled portion of the trial.
<i>Clostridium septicum</i> α-toxin activates the NLRP3 inflammasome by engaging GPI-anchored proteins
Authors: Weidong Jing, Jordan Lo Pilato, Callum Kay, Shouya Feng, Daniel Enosi Tuipulotu, Anukriti Mathur, Cheng Shen, Chinh Ngo, Anyang Zhao, Lisa A. Miosge, Sidra A. Ali, Elizabeth E. Gardiner, Milena M. Awad, Dena Lyras, Avril A. B. Robertson, Nadeem O. Kaakoush, Si Ming Man
Journal: Science Immunology (2022)

Clostridium species are a group of Gram-positive bacteria that cause diseases in humans, such as food poisoning, botulism, and tetanus. Here, we analyzed 10 different Clostridium species and identified that Clostridium septicum , a pathogen that causes sepsis and gas gangrene, activates the mammalian cytosolic inflammasome complex in mice and humans. Mechanistically, we demonstrate that α-toxin secreted by C. septicum binds to glycosylphosphatidylinositol (GPI)–anchored proteins on the host plasma membrane, oligomerizing and forming a membrane pore that is permissive to efflux of magnesium and potassium ions. Efflux of these cytosolic ions triggers the activation of the innate immune sensor NLRP3, inducing activation of caspase-1 and gasdermin D, secretion of the proinflammatory cytokines interleukin-1β and interleukin-18, pyroptosis, and plasma membrane rupture via ninjurin-1. Furthermore, α-toxin of C. septicum induces rapid inflammasome-mediated lethality in mice and pharmacological inhibition of the NLRP3 inflammasome using MCC950 prevents C. septicum –induced lethality. Overall, our results reveal that cytosolic innate sensing of α-toxin is central to the recognition of C. septicum infection and that therapeutic blockade of the inflammasome pathway may prevent sepsis and death caused by toxin-producing pathogens.
Paired Tumor-Germline Testing as a Driver in Better Cancer Care
Authors: John W. Henson
Journal: JAMA Network Open (2022)

Timothy A. Yap, MD, PhD; Arya Ashok, PhD; Jessica Stoll, MS; Elizabeth Mauer, MS; Vanessa M. Nepomuceno, PhD; Kimberly L. Blackwell, MD; Judy E. Garber, MD, MPH; Funda Meric-Bernstam, MD
Chronic hepatitis E: Advancing research and patient care
Authors: Zhongren Ma, Robert A. de Man, Nassim Kamar, Qiuwei Pan
Journal: Journal of Hepatology (2022)

The hepatitis E virus (HEV) was initially thought to exclusively cause acute hepatitis. However, the first diagnosis of chronic hepatitis E in transplant recipients in 2008 profoundly changed our understanding of this pathogen. We have now begun to understand that specific HEV genotypes can cause chronic infection in certain immunocompromised populations. Over the past decade, dedicated clinical and experimental research has substantiated knowledge on the epidemiology, transmission routes, pathophysiological mechanisms, diagnosis, clinical features and treatment of chronic HEV infection. Nevertheless, many gaps and major challenges remain, particularly regarding the translation of knowledge into disease prevention and improvement of clinical outcomes. This article aims to highlight the latest developments in the understanding and management of chronic hepatitis E. More importantly, we attempt to identify major knowledge gaps and discuss strategies for further advancing both research and patient care.
Hypocellular myelodysplastic syndromes (h-MDS): from clinical description to immunological characterization in the Italian multi-center experience
Authors: Giulia Calabretto, Enrico Attardi, Antonella Teramo, Valentina Trimarco, Samuela Carraro, Sandra Mossuto, Gregorio Barilà, Cristina Vicenzetto, Vanessa Rebecca Gasparini, Monica Crugnola, Pasquale Niscola, Antonella Poloni, Valentina Giai, Valentina Gaidano, Carlo Finelli, Roberta Bertorelle, Cinzia Candiotto, Marco Pizzi, Gianni Binotto, Monica Facco, Fabrizio Vianello, Livio Trentin, Gianpietro Semenzato, Renato Zambello, Valeria Santini
Journal: Leukemia (2022)

Myelodysplastic Syndromes (MDS) are a highly heterogeneous group of blood neoplasias characterized by myeloid dysplasia, ineffective hematopoiesis and increased risk of progression to acute myeloid leukemia [1].We focused on hypocellular-MDS (h-MDS), a rare subtype accounting for 10-15% of MDS patients, that is defined by an age-adjusted reduction of bone marrow (BM) cellularity or, according to Aplastic Anemia definition, by a BM cellularity <30% [2].Although the WHO classification of myeloid neoplasms and acute leukemia does not recognize h-MDS as a distinct entity, these patients are typically younger and characterized by more severe cytopenias, higher transfusion dependence and lower blast percentages as compared to normo/hypercellular MDS (n-MDS) [3][4][5].Data on h-MDS outcome, instead, are still inconsistent [4,6].Beside these clinical features, h-MDS share molecular characteristics, including karyotype abnormalities, that suggest a common underlying pathogenesis [4,5].A barely understood biology, ill-defined diagnostic criteria and the lack of conclusive prognostic data hindered the establishment of specific treatment guidelines for h-MDS.The evaluation of clinical outcome following immunosuppressive therapy (IST) in MDS patients indicated peculiar responses in the hypoplastic category [7,8], supporting a pathogenetic role of immune system alterations.In this regard, the immunological characterization of h-MDS should help to improve the risk stratification of patients and choice of therapy.
Covid-19: Sexually transmitted diseases surged in US during pandemic
Authors: Janice Hopkins Tanne
Journal: BMJ (2022)

Sexually transmitted diseases surged in US during pandemicJanice Hopkins Tanne US cases of gonorrhoea, syphilis, and congenital syphilis declined at the beginning of the covid-19 pandemic in 2020, but then rose markedly for the rest of the year, the US Centers for Disease Control and Prevention (CDC) has reported.Chlamydia declined slightly.The CDC cautioned that the data may be an undercount because of the pandemic. 1 -5 3
Inability to phosphorylate Y88 of p27Kip1 enforces reduced p27 protein levels and accelerates leukemia progression
Authors: Heidelinde Jäkel, Martin Taschler, Karin Jung, Christina Weinl, Fragka Pegka, Michael Keith Kullmann, Silvio Roland Podmirseg, Sayantanee Dutta, Markus Moser, Ludger Hengst
Journal: Leukemia (2022)

Abstract The cyclin-dependent kinase (CDK) inhibitor p27 Kip1 regulates cell proliferation. Phosphorylation of tyrosine residue 88 (Y88) converts the inhibitor into an assembly factor and activator of CDKs, since Y88-phosphorylation restores activity to cyclin E,A/CDK2 and enables assembly of active cyclin D/CDK4,6. To investigate the physiological significance of p27 tyrosine phosphorylation, we have generated a knock-in mouse model where Y88 was replaced by phenylalanine (p27-Y88F). Young p27-Y88F mice developed a moderately reduced body weight, indicative for robust CDK inhibition by p27-Y88F. When transformed with v-ABL or BCR::ABL1 p190 , primary p27-Y88F cells are refractory to initial transformation as evidenced by a diminished outgrowth of progenitor B-cell colonies. This indicates that p27-Y88 phosphorylation contributes to v-ABL and BCR::ABL1 p190 induced transformation. Surprisingly, p27-Y88F mice succumbed to premature v-ABL induced leukemia/lymphoma compared to p27 wild type animals. This was accompanied by a robust reduction of p27-Y88F levels in v-ABL transformed cells. Reduced p27-Y88F levels seem to be required for efficient cell proliferation and may subsequently support accelerated leukemia progression. The potent downregulation p27-Y88F levels in all leukemia-derived cells could uncover a novel mechanism in human oncogenesis, where reduced p27 levels are frequently observed.
Liver cancer in severe alpha-1 antitrypsin deficiency: who is at risk?
Authors: Malin Fromme, Pavel Strnad
Journal: European Respiratory Journal (2022)

We would like to congratulate Hiller et al . [1] on their systematic analysis of cancer occurrence in a large prospective cohort of individuals with severe alpha-1 antitrypsin deficiency (AATD; Pi*ZZ genotype). The data on development of hepatic cancer are of particular relevance for two reasons: 1) the current evidence is low and controversial [2]; and 2) the early detection of liver cancer is associated with markedly improved prognosis and, because of that, surveillance programmes are recommended in high risk individuals [3, 4]. The stage of liver fibrosis needs to be considered when evaluating the individual liver cancer risk https://bit.ly/3jVy5AN
C3aR costimulation enhances the antitumor efficacy of CAR-T cell therapy through Th17 expansion and memory T cell induction
Authors: Peilong Lai, Xiaomei Chen, Yulian Wang, Jinghua Wang, Yuchen Zhang, Suxia Geng, Peng Li, Xin Du, Jianyu Weng, Duanqing Pei
Journal: Journal of Hematology & Oncology (2022)

Abstract Although chimeric antigen receptor (CAR)-modified adoptive T cell therapy is a promising immunotherapy for hematological malignancies, the efficacy improvement in relapsed/refractory acute lymphoblastic leukemia (ALL) with extramedullary infiltration and in multiple myeloma (MM) is still warranted. Since C3aR activation can promote the expansion of tumor-killing Th17 cells, we hypothesized that incorporating C3aR as a costimulatory domain would augment the antitumor activity of CAR-T. In this study, we introduced the C3aR domain into a CAR and generated BB-ζ-C3aR CAR-T targeting CD19 or BCMA. These new CAR-T exhibited a potent cytolytic ability to eradicate tumor cells expressing CD19 or BCMA in vitro. When administered intravenously to ALL or MM xenograft mouse models, BB-ζ-C3aR CAR-T reduced the tumor burden and improved the survival rate. Of note, these CAR-T could effectively eradicate subcutaneous CD19 + tumor cells, highlighting the therapeutic potential in extramedullary leukemia. Mechanistically, BB-ζ-C3aR CAR-T tended to exhibit a Th17 phenotype favoring tumor killing and suppressed Tregs. In addition, the induction of memory T cell in the BB-ζ-C3aR CAR-T cells indicated their long-term effects. Together, our findings suggest that the application of C3aR costimulation boosts the ability of CAR-T to eradicate aggressive tumor cells via Th17 expansion and memory T cell induction.
Direct oral anticoagulant versus low molecular weight heparin for the treatment of cancer-associated venous thromboembolism: 2022 updated systematic review and meta-analysis of randomized controlled trials
Authors: Corinne Frere, Dominique Farge, Deborah Schrag, Pedro H. Prata, Jean M. Connors
Journal: Journal of Hematology & Oncology (2022)

Abstract International clinical practice guidelines have progressively endorsed direct oral anticoagulants (DOACs) as an alternative to low-molecular-weight heparins (LMWHs) monotherapy for the initial and long-term treatment of cancer-associated thrombosis (CAT). Several new randomized controlled trials (RCTs) have recently reported additional results on the safety and efficacy of DOACs in this setting. We performed an updated meta-analysis of all publicly available data from RCTs comparing DOACs with LMWHs for the treatment of CAT. Six RCTs enrolling 3690 patients with CAT were included. Compared with LMWHs, DOACs significantly decreased the risk of CAT recurrence (RR, 0.67; 95%CI, 0.52–0.85), with a non-significant increase in the risk of major bleeding (RR, 1.17; 95%CI, 0.82–1.67), a significant increase in the risk of clinically relevant nonmajor bleeding (RR 1.66; 95%CI, 1.31–2.09) and no difference in all-cause mortality rates. These results increase the level of certainty of available evidence supporting the use of DOACs as an effective and safe option for the treatment of CAT in selected cancer patients.
Current and future diagnostic and treatment strategies for patients with invasive lobular breast cancer
Authors: K. Van Baelen, T. Geukens, M. Maetens, V. Tjan-Heijnen, C.J. Lord, S. Linn, F.-C. Bidard, F. Richard, W.W. Yang, R.E. Steele, S.J. Pettitt, C. Van Ongeval, M. De Schepper, E. Isnaldi, I. Nevelsteen, A. Smeets, K. Punie, L. Voorwerk, H. Wildiers, G. Floris, A. Vincent-Salomon, P.W.B. Derksen, P. Neven, E. Senkus, E. Sawyer, M. Kok, C. Desmedt
Journal: Annals of Oncology (2022)

Invasive lobular breast cancer (ILC) is the second most common type of breast cancer after invasive breast cancer of no special type (NST), representing up to 15% of all breast cancers.
Thirty-Year Time Trends in Diabetic Retinopathy and Macular Edema in Youth With Type 1 Diabetes
Authors: Digby W. Allen, Gerald Liew, Yoon Hi Cho, Alison Pryke, Janine Cusumano, Stephen Hing, Albert K. Chan, Maria E. Craig, Kim C. Donaghue
Journal: Diabetes Care (2022)

OBJECTIVE To examine trends in diabetic retinopathy (DR) and diabetic macular edema (DME) in adolescents with type 1 diabetes between 1990 and 2019. RESEARCH DESIGN AND METHODS We analyzed 5,487 complication assessments for 2,404 adolescents (52.7% female, aged 12–20 years, diabetes duration &amp;gt;5 years), stratified by three decades (1990–1999, 2000–2009, 2010–2019). DR and DME were graded according to the modified Airlie House classification from seven-field stereoscopic fundal photography. RESULTS Over three decades, the prevalence of DR was 40, 21, and 20% (P &amp;lt; 0.001) and DME 1.4, 0.5, and 0.9% (P = 0.13), respectively, for 1990–1999, 2000–2009, and 2010–2019. Continuous subcutaneous insulin infusion (CSII) use increased (0, 12, and 55%; P &amp;lt; 0.001); mean HbA1c was bimodal (8.7, 8.5, and 8.7%; P &amp;lt; 0.001), and the proportion of adolescents meeting target HbA1c &amp;lt;7% did not change significantly (8.3, 7.7, and 7.1%; P = 0.63). In multivariable generalized estimating equation analysis, DR was associated with 1–2 daily injections (odds ratio 1.88, 95% CI 1.42–2.48) and multiple injections in comparison with CSII (1.38, 1.09–1.74); older age (1.11, 1.07–1.15), higher HbA1c (1.19, 1.05–1.15), longer diabetes duration (1.15, 1.12–1.18), overweight/obesity (1.27, 1.08–1.49) and higher diastolic blood pressure SDS (1.11, 1.01–1.21). DME was associated with 1–2 daily injections (3.26, 1.72–6.19), longer diabetes duration (1.26, 1.12–1.41), higher diastolic blood pressure SDS (1.66, 1.22–2.27), higher HbA1c (1.28, 1.03–1.59), and elevated cholesterol (3.78, 1.84–7.76). CONCLUSIONS One in five adolescents with type 1 diabetes had DR in the last decade. These findings support contemporary guidelines for lower glycemic targets, increasing CSII use, and targeting modifiable risk factors including blood pressure, cholesterol, and overweight/obesity.
The Need for Integrating Addiction Medicine and Hepatology
Authors: Lorenzo Leggio, M. Katherine Jung
Journal: JAMA Network Open (2022)

Augustin G. L. Vannier, BA; Jessica E. S. Shay, MD, PhD; Vladislav Fomin, MD; Suraj J. Patel, MD, PhD; Esperance Schaefer, MD, MPH; Russell P. Goodman, MD, PhD; Jay Luther, MD
Lingual Mucosal Graft Ureteroplasty for Long Proximal Ureteral Stricture: 6 Years of Experience with 41 Cases
Authors: Chaoqi Liang, Jianli Wang, Bo Hai, Yujie Xu, Jinmin Zeng, Shuaishuai Chai, Jiawei Chen, Hao Zhang, Xincheng Gao, Gong Cheng, Xiong Yang, Teng Hou, Wencheng Li, Xingyuan Xiao, Bing Li
Journal: European Urology (2022)

Management of a long proximal ureteral stricture is challenging. Lingual mucosal graft ureteroplasty (LMGU) is a novel minimally invasive technique for ureteral reconstruction that avoids the morbidity of bowel interposition or autotransplantation.To evaluate the long-term effectiveness of LMGU for managing long, complex proximal ureteral strictures in a multi-institutional cohort of patients.This retrospective study involved data for 41 patients treated with LMGU at three centers between June 2015 and January 2021.LMGU was performed using either an onlay ureteroplasty in which the diseased ureter was incised ventrally and repaired with a lingual mucosal graft (LMG) to widen the ureteral lumen, or an augmented anastomotic technique in which the obliterated segment of the ureter was excised and reanastomosed primarily on dorsal side, and an LMG was placed on the ventral side.Pre-, intra-, and postoperative variables and outcomes were assessed. A descriptive statistical analysis was performed.Of 41patients, 40 were operated with laparoscopic procedures and one with a robot. Twenty-four (59%) patients underwent an onlay ureteroplasty, and 17 (41%) underwent an augmented anastomotic ureteroplasty. The reconstructed ureter was wrapped with omentum in 90% of cases. The median (range) stricture length was 4.8 cm (2.0-8.0), operative time was 166 min (98-306), and estimated blood loss was 65 ml (15-220). No open conversions and intraoperative complications occurred. At a median follow-up of 35 mo (range 13-80), the overall success rate was 97.6% (40/41).LMGU is a safe, feasible, and effective long-term technique for managing long, complex proximal ureteral strictures.We reported a novel technique for long proximal complex ureteral strictures using an onlay lingual mucosal graft (LMG). Our 6-yr outcomes demonstrate that onlay LMG ureteroplasty is a safe, feasible, and effective long-term procedure for ureteral reconstruction.
Pneumococcal urinary antigen testing for antimicrobial guidance in community-acquired pneumonia–A register-based cohort study
Authors: Simon Athlin, Anders Magnuson, Carl Spindler, Jonas Hedlund, Kristoffer Strålin, Pontus Nauclér
Journal: Journal of Infection (2022)

To evaluate the effect of pneumococcal urinary antigen test (UAT) usage on broad-spectrum antibiotic treatment in community-acquired pneumonia (CAP).Patients admitted to 32 Swedish hospitals between 2011 and 2014 were retrospectively included from the Swedish National Quality Register of CAP. Using propensity score matched data, stratified by CRB-65 score, we studied the effect of performing UAT and of positive test results on treatment with broad-spectrum β-lactam monotherapy (BSBM) and antibiotics with coverage for atypical bacteria compared to narrow-spectrum β-lactam monotherapy (NSBM).UAT was performed for 4,995/14,590 (34.2%) patients, 603/4,995 (12.1%) of whom had positive test results. At day three, performing UAT was not associated with decreased use of BSBM (OR 1.07, 95% CI 0.94-1.23) but was associated with increased atypical coverage among patients with CRB-65 score 2 (OR 1.47, 95% CI 1.06-2.02). A positive UAT was associated with decreased BSBM use (OR 0.39, 95% CI 0.25-0.60) and decreased atypical coverage (OR 0.25, 95% CI 0.16-0.37), predominantly in non-severe CAP. At day one, performing UAT was associated with atypical coverage among patients with CRB-65 scores 2 (OR 2.60, 95% CI 1.69-3.98) and 3-4 (OR 3.69, 95% CI 1.55-8.79), and a positive test reduced the odds of BSBM treatment among CRB-65 score 3-4 patients (OR 3.49, 95% CI 1.02-12.0).Performing UAT had no overall effect on decreasing the use of BSBM treatment by day three of hospitalization, yet non-severely ill patients with positive UAT results were less likely to be treated with BSBM and antibiotics with atypical coverage.
The role of hypoxia in the pathophysiology of chronic rhinosinusitis
Authors: Bing Zhong, Jun Jie Seah, Feng Liu, Luo Ba, Jintao Du, De Yun Wang
Journal: Allergy (2022)

Abstract Chronic rhinosinusitis (CRS) is a chronic inflammatory disease of the nasal cavity characterized by excessive nasal mucus secretion and nasal congestion. The development of CRS is related to pathological mechanisms induced by hypoxia. Under hypoxic conditions, the stable expression of both Hypoxia inducible factor‐1 (HIF‐1) α and HIF‐2α are involved in the immune response and inflammatory pathways of CRS. The imbalance in the composition of nasal microbiota may affect the hypoxic state of CRS and perpetuate existing inflammation. Hypoxia affects the differentiation of nasal epithelial cells such as ciliated cells and goblet cells, induces fibroblast proliferation, and leads to epithelial‐mesenchymal transition (EMT) and tissue remodeling. Hypoxia also affects the proliferation and differentiation of macrophages, eosinophils, basophils, and mast cells in sinonasal mucosa, and thus influences the inflammatory state of CRS by regulating T cells and B cells. Given the multifactorial nature in which HIF is linked to CRS, this study aims to elucidate the effect of hypoxia on the pathogenic mechanisms of CRS.